Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model.
Lung cancer is the leading cause of cancer deaths in the United States. In addition to genetic abnormalities induced by cigarette smoke, several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lungs, have an increased risk of lung cancer (1.3- to 4.9-fold) compared to smokers without COPD. This suggests a link between chronic airway inflammation and lung carcinogenesis, independent of tobacco smoke exposure. We studied this association by assaying the inflammatory impact of products of nontypeable Haemophilus influenzae, which colonizes the airways of patients with COPD, on lung cancer promotion in mice with an activated K-ras mutation in their airway epithelium. Two new mouse models of lung cancer were generated by crossing mice harboring the LSL-K-ras(G12D) allele with mice containing Cre recombinase inserted into the Clara cell secretory protein (CCSP) locus, with or without the neomycin cassette excised (CCSP(Cre) and CCSP(Cre-Neo), respectively). Lung lesions in CCSP(Cre-Neo)/LSL-K-ras(G12D) and CCSP(Cre)/LSL-K-ras(G12D) mice appeared at 4 and 1 month of age, respectively, and were classified as epithelial hyperplasia of the bronchioles, adenoma, and adenocarcinoma. Weekly exposure of CCSP(Cre)/LSL-K-ras(G12D) mice to aerosolized nontypeable Haemophilus influenzae lysate from age 6-14 weeks resulted in neutrophil/macrophage/CD8 T-cell-associated COPD-like airway inflammation, a 3.2-fold increase in lung surface tumor number (156 +/- 9 versus 45 +/- 7), and an increase in total lung tumor burden. We conclude that COPD-like airway inflammation promotes lung carcinogenesis in a background of a G12D-activated K-ras allele in airway secretory cells.
Moghaddam
Seyed Javad
SJ
Department of Pulmonary Medicine, University of Texas M. D. Anderson Cancer Center, 2121 W. Holcombe Boulevard, Suite 703F, Houston, TX 77030, USA. smoghadd@mdanderson.org
Li
Huaiguang
H
Cho
Sung-Nam
SN
Dishop
Megan K
MK
Wistuba
Ignacio I
II
Ji
Lin
L
Kurie
Jonathan M
JM
Dickey
Burton F
BF
Demayo
Francesco J
FJ
D000336:Aerosols; D000818:Animals; D001426:Bacterial Proteins; D001992:Bronchoalveolar Lavage Fluid; D019070:Cell Lineage; D049109:Cell Proliferation; D018925:Chemokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D008175:Lung Neoplasms / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D018272:Porins; D011230:Precancerous Conditions / Q000150:complications* / Q000382:microbiology / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000382:microbiology / Q000473:pathology*; D016019:Survival Analysis; D019076:Transgenes; D047368:Tumor Burden; D014598:Uteroglobin / Q000378:metabolism
D000336:Aerosols; D001426:Bacterial Proteins; D018925:Chemokines; D016328:NF-kappa B; D018272:Porins; C556390:Scgb1a1 protein, mouse; C451502:ompP2 protein, Haemophilus influenzae; D014598:Uteroglobin; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)